Type 2 diabetes mellitus is a polygenic, heterogeneous disorder characterized by the presence of both beta cell dysfunction and insulin resistance. Although a clear genetic component exists for the common forms of human type 2 diabetes, few susceptibility genes have been identified. The purpose of the parent K23 grant is to elucidate the genetic underpinnings of insulin secretion through well-controlled prospective clinical studies of several candidate gene variants. The purpose of this R03 is to extend these studies by investigating a new gene variant in the betacellulin gene that my group has recently identified. This variant associates with type 2 diabetes and may affect insulin secretion. The proposed studies will help to clarify this new betacellulin variant's role in insulin secretion. Furthermore, despite the concurrences that type 2 diabetes is a polygenic disorder, few studies have been performed which address gene-gene interactions. To test our hypotheses, we propose to prospectively recruit non-diabetic subjects with the betacellulin variant, individually and in combination with other variants (BETA2/NeuroD Ala45Thr, IRS2 GIy1057Asp, b3AR Trp64Arg) and characterize insulin secretion using the insulin-modified frequently sampled intravenous glucose tolerance test, insulin oscillation studies, and proinsulin levels. By elucidating the effects of the betacellulin gene variant, individually and in combination with these other variants on insulin secretion, we will provide critical insight into the underlying molecular mechanisms of a-cell dysfunction and the polygenic nature of type 2 diabetes. In turn, this will lead to new preventative strategies and new molecular targets for the design and effective therapeutic agents.